The Research Center for Pharmacology and Drug Toxicology brings together a group of highly experienced investigators with a shared interest in the role of oxygenation of lipids and oxidative stress in disease pathogenesis as a basis for the identification of new pharmacologic strategies for treatment of human disease. The Center is comprised of five research projects and two cores. The proposed research in Project 1 is an evolution of our previous studies in the Center which elucidated that acetaminophen inhibits hemoprotein redox cycling induced lipid peroxidation. Our new studies will investigate the ability of acetaminophen and related compounds to prevent apoptosis by inhibiting cytochrome c redox cycling induced oxidation of cardiolipin, an essential component of the apoptotic cascade. The proposed research in Project 2 is comprised of two clinical projects. One will evaluate the ability of acetaminophen to inhibit hemoglobin redox cycling induced lipid peroxidation in patients with subarachnoid hemorrhage and the second project will evaluate the ability of acetaminophen to inhibit hemoglobin and myoglobin induced oxidative stress in patients undergoing cardiopulmonary bypass surgery. The proposed research in Project 3 will explore the selective oxygenation of endocannabinoids by cyclooxygenase-2 to form 2-arachidonoylethanolamide and 2-arachidonoylglycerol and their substrate- selective inhibition by low concentrations of non-steroidal anti-inflammatory drugs (NSAIDs). 'The proposed research in Project 4 will explore approaches to therapeutically modulate levels of endothelial cell tetrahydrobiopterin as a means to prevent oxidative stress due to uncoupling of nitric oxide synthase. The proposed research in Project 5 will explore the mechanisms underlying the biosynthesis of leukotriene-A type fatty acid epoxides, which are key intermediates in the formation of pro-inflammatory leukotrienes and eoxins and the pro-resolving lipoxins, resolvins, protectins, and maresins. RELEVANCE: It is anticipated that these studies will lead to (a) effective novel pharmacologic approaches to prevent apoptotic death in settings such as myocardial infarction and stroke and hemoprotein mediated oxidative damage in settings of subarachnoid hemorrhage and cardiopulmonary bypass surgery, (b) new insights into some of the unexplained actions of NSAID's, (c) new therapeutic approaches to improve vascular function by enhancing levels of tetrahydrobiopterin and (d) new insights into potential ways to pharmacologically modulate the formation of resolvins, protectins, lipoxins, and maresins.